Swallowable capsule and method for stimulating incretin production within the intestinal tract

ABSTRACT

Embodiments of the invention provide apparatus and methods for stimulating L cells in the intestinal tract to produce incretins for the treatment of conditions including diabetes and obesity. Many embodiments provide a method and apparatus for the treatment of diabetes by electrically stimulating L-cells to secrete incretins to stimulate or otherwise modulate the production of insulin. Particular embodiments provide a swallowable capsule for stimulating L-cells in the intestinal tract as the capsule moves through the tract. The capsule can include two or more electrodes for providing electrical stimulation to L-cells, a power source for powering one or more components of the capsule, a sensor for sensing the location of the capsule in the intestinal tract; a controller and a waveform generator for generating the electrical signals emitted by the electrodes to stimulate the L-cells to secrete incretins such as GLP-1 to stimulate insulin production for glucose regulation of diabetic conditions.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 15/192,928, filed Jun. 24, 2016, now U.S. Pat. No. 9,643,005,which is a continuation of U.S. patent application Ser. No. 14/599,350,filed Jan. 16, 2015, now U.S. Pat. No. 9,403,002, which is acontinuation of U.S. patent application Ser. No. 14/273,917, filed May9, 2014, now U.S. Pat. No. 8,958,879, which is a continuation of U.S.patent Ser. No. 14/179,215, filed Feb. 12, 2014, now U.S. Pat. No.8,781,591, which is a divisional of U.S. patent application Ser. No.12/849,574, filed Aug. 3, 2010, now U.S. Pat. No. 8,682,440; whichclaims the benefit of Provisional Application No. 61/273,389, filed Aug.3, 2009; the entire contents of which are incorporated herein byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

Embodiments described herein relate to apparatus and methods forelectrically stimulating cells in the GI system to produce polypeptidesfor the treatment of various conditions such as diabetes and obesity.More specifically, embodiments of the invention relate to treatment ofdiabetes by electrically stimulating cells in the gastro-intestinal (GI)system to produce glucose regulating hormones such as incretins.

Due to the increasing consumption of high fat and/or high caloric foodsfound in the western diet, there has been an epidemic in the UnitedStates and other developed countries of diabetes and obesity. Diabetesis a disease in which the body does not produce enough, or properlyrespond to, insulin, a hormone produced in the pancreas. Insulin isneeded to turn sugar and other food into energy. In diabetes, the bodyeither doesn't make enough insulin or can't use its own insulin as wellas it should, or both. This causes sugar to accumulate in the blood,often leading to various complications. The American DiabetesAssociation reported in 2009 that there are 23.6 million children andadults in the United States (equal to about 7.8% of the totalpopulation) who have diabetes. While an estimated 17.9 million in the USalone have been diagnosed with diabetes, nearly one in four (5.7million) diabetics are unaware that they have the disease.

The main types of diabetes include type 1, type 2 and gestationaldiabetes. Type 1 diabetes results from the body's failure to produceinsulin. It is estimated that 5-10% of Americans who are diagnosed withdiabetes have type 1 diabetes. Presently almost all persons with type 1diabetes must take insulin injections.

Type 2 diabetes results from a condition in which the body fails to useinsulin properly, combined with a relative insulin deficiency. MostAmericans who are diagnosed with diabetes have type 2 diabetes. Manypeople destined to develop type 2 diabetes spend many years in a stateof pre-diabetes: Termed “America's largest healthcare epidemic, acondition that occurs when a person's blood glucose levels are higherthan normal but not high enough for a diagnosis of type 2 diabetes. Asof 2009 there were 57 million Americans who have pre-diabetes. In thedeveloped world, diabetes is the most significant cause of adultblindness in the non-elderly and the leading cause of non-traumaticamputation in adults. Furthermore, diabetic nephropathy is the mainillness requiring renal dialysis in the United States.

Most forms of diabetes have been treatable, in part, since insulinbecame medically available in the 1920's. Currently, many diabeticsmonitor their blood glucose using blood glucose meters and givethemselves insulin injections one or more times a day. However, thisapproach has many complications due to the under or over delivery ofinsulin as well as a long-term inability to regulate blood glucose.Acute complications including hypoglycemia, diabetic ketoacidosis, ornon-ketotic hyperosmolar coma may occur if the disease is not adequatelycontrolled. Serious long-term complications include cardiovasculardisease, chronic renal failure, retinal damage (which may lead toblindness), nerve damage, and micro-vascular damage (which may causeerectile dysfunction and poor wound healing). Poor healing of wounds,particularly of the feet, can lead to gangrene, and possibly toamputation.

Other forms of drug therapy are also available, such as Metformin (knownas GLUCOPHAGE). However, this drug is only indicated for the treatmentof type II non-insulin dependent diabetes and has a number of sideeffects including various gastro-intestinal side effects. Also, it maynot be used with patients who have renal disease. Other forms oftreatment include implantabable insulin pumps; however, these are costlyand ultimately become rejected by the body. Thus there is a need forimproved forms of treatment of diabetes and other glucose regulationdisorders.

Obesity, defined as a body mass index (BMI) of greater than 30, is amajor health concern in the United States and other countries. It hasbeen estimated that one in three Americans and more than 300 millionpeople world-wide are obese. Complications of obesity include manyserious and life-threatening diseases including hypertension, diabetes,coronary artery disease, stroke, congestive heart failure, pulmonaryinsufficiency, multiple orthopedic problems, various cancers and amarkedly decreased life expectancy. Many therapies have been attemptedfor the treatment of obesity including diets, drugs and more invasivetreatments such as stomach stapling. However, many fail due to theinability to invoke the satiety signal pathways which indicate to aperson when they are full. Research now indicates that many foods beingsupplied by the foods industry, including those high in salt, sugar andfat, invoke a strong signal response in the brain to keep eating. Thusthere is a need for improved forms of obesity treatment including thosewhich can stimulate satiety signals and/or appetite suppression signalsto cause the person to stop eating or otherwise suppress their appetite.

BRIEF SUMMARY OF THE INVENTION

Embodiments of the invention provide apparatus and methods forstimulating L-cells of the small intestine to produce incretins andother peptides for the treatment of various diseases and conditionsincluding diabetes and obesity. Many embodiments provide a method andapparatus for the treatment of obesity, diabetes and other glucoseregulation disorders by electrically stimulating L-cells to secreteglucagon-like proteins (GLP, also referred to herein as glucagon-likepeptides) and other incretins to stimulate the production of insulin.Particular embodiments provide a swallowable capsule for electricallystimulating L-cells in the intestinal tract to secrete GLPs as thecapsule moves through the intestinal tract. Embodiments of the capsulecan include two or more electrodes for providing electrical stimulationto L-cells, a sensor for sensing the location of the capsule in theintestinal tract, a power source such as a battery for powering one moreelectrical components within the capsule, and a controller forcontrolling one or more operations of the capsule and a signal/waveformgenerator for generating the electrical signals delivered to the tissueby the electrodes to stimulate the L-cells to produce incretins such asglucagon-like peptide-1 (GLP-1). The signals will typically comprise awaveform such as a square-wave having a selectable pulse duration andmay be generated by a signal/waveform generator integral to or coupledto the controller. Desirably, the signal is configured such that it willstimulate the L-cells to secrete incretins, such as GLP-1, but will notcause peristaltic contractions of the intestinal site near the capsuleor any other location in the intestinal tract. However, in someembodiments, the waveform generator can also be configured to producetwo waveforms, one waveform for stimulating the L-cells without causingperistaltic contractions and a second waveform for causing peristalticcontractions so as to advance the capsule along the intestinal tract. Inthese later embodiments, the capsule can include an accelerometer fordetecting when the capsule has stopped moving or is moving below adesired velocity threshold. In use, these latter embodiments allow forthe capsule to be advanced in patients who have a very slow movingintestinal tract such as those patients who have intestinal neuropathyor other related condition such as intestinal necrosis. When thecontroller receives an input from the accelerometer indicating that thecapsule has stopped or is moving too slowly, the controller can send asignal for the waveform generator to generate the second waveformcausing peristaltic contraction of the intestine in the region near thecapsule which in turn propels the capsule distally through theintestine. The process can be repeated as needed with selectable delaysto allow for the refractory period of the peristaltic contraction.

The electrodes will typically include at least one pair of electrodeswhich can be positioned in a variety of locations and orientations onthe surface of the capsule. This can include in a lengthwise fashionwith respect to the longitudinal axis or radial axis of capsule. Inparticular embodiments, the electrodes can comprise one or more pairs ofring electrodes which are placed on the surface capsule. The electrodescan comprise various conductive metals known in the art includingsilver-silver chloride or platinum, for example. The spacing of theelectrodes may be configured to minimize electrical stimulation oftissue subjacent the mucosal layer of intestinal tract. In particularembodiments, the spacing can be configured to limit the electricalstimulation of the intestinal wall to a depth of 5 mm or less.

In various embodiments, the at least one sensor can include one or moreof a pH sensor for detecting the passage of the capsule from the stomachinto the small intestine and a pressure sensor for sensing theperistaltic contraction of the intestines so as to detect when thecapsule is in the intestine (independent of or in combination with aninput from the pH sensor). The pressure sensor can also be used todetect when the intestine is in contact with capsule (e.g., when it'sbeing squeezed during a peristaltic contraction) and thus when toinitiate a period of stimulation. Particular embodiments can includeboth pH and pressure sensors so as to determine a change in pH fromstomach to intestine as well as a peristaltic contraction providing anincreased level of accuracy in determining the position of the sensorwithin the tract. Still other sensors are contemplated, such astemperature, O.sub.2, CO.sub.2, optical sensors, etc. The inputs frommultiple sensors may also be combined to come up with an aggregatesensory input for the controller to determine the position of thecapsule. In various embodiments, sensor conditioning circuitry (e.g.,band pass filters) can be coupled to the controller to condition thesensor signals prior to being inputted to the controller.

In an exemplary embodiment of a method of use, the swallowable capsuleof the present invention can be used to stimulate L-cell secretion ofvarious proteins such as GLPs so as to facilitate insulin release and/orenhance its activity in the body. In these and other relatedembodiments, the user may swallow the capsule before, during or after ameal. Upon ingestion, the swallowable capsule makes its way through thestomach and into the small intestine. Sensors in the capsule allow itsrelative location in the body to be detected. For example, sensors forpH, pressure, or other pertinent indicia allow the capsule to determinewhen it has reached the small intestine. Once in the small intestine,the swallowable capsule is activated by a controller (typically withinthe capsule) to provide electrical stimulation so that L cells of thesmall intestine secrete GLP-1 or other incretins (GIP, PYY, etc.). TheGLP-1 and/or other incretins then elicit secretion of insulin and/orfacilitate the body's use of insulin. Activation of the swallowablecapsule to provide electrical stimulation may, for example, be directedby internal instructions and/or programs in the swallowable capsule, ormay be provided by external control of the swallowable capsule.Preferably, the swallowable capsule is ingested shortly before or with ameal so that the stimulation of secretion of GLP-1 and/or otherincretins is coordinated with the absorption of nutrients from thedigesting food so that subsequent insulin production is also coordinatedwith the influx of glucose, fats and other nutrients into the bloodstream. In this way, the patient's blood glucose levels can becontrolled to more closely approximate those of a normal non-diabeticindividual following a meal.

Further details of these and other embodiments and aspects of theinvention are described more fully below with reference to theaccompanying figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a view showing the small intestine and the distribution ofL-cells along the intestinal wall.

FIG. 2 is a cross sectional view of the intestine showing the positionof the L-cell in the intestinal wall.

FIG. 3 is a schematic view illustrating the biochemical andphysiological function of the L-cell including hormonal secretion andintracellular signaling.

FIG. 4 is a lateral view showing an embodiment of the swallowablecapsule of the present invention.

FIG. 5 is a cross sectional view illustrating use of an embodiment ofthe swallowable capsule in the intestinal tract to stimulate L-cells tosecrete incretins.

FIG. 6 is a lateral view showing the gap between the electrodes of anembodiment of the swallowable capsule.

FIGS. 7a-7d are views showing different embodiments for configurationsof electrodes on the capsule; FIG. 7a is a lateral view showing anembodiment of the capsule having ring electrodes; FIG. 7b is a lateralview showing an embodiment having laterally oriented electrodes; FIG. 7c, is a cross sectional view showing an embodiment having multiplelaterally oriented electrodes; FIG. 7d is a lateral view showing anembodiment having both ring and laterally oriented electrodes.

FIG. 8 is a block diagram showing an embodiment of an electronicarchitecture for controlling one or more functions of the swallowablecapsule.

FIGS. 9a-9d are lateral views illustrating use of an electricallystimulating waveform emitted from the capsule to evoke peristaltic wavesto move the capsule through the intestinal tract.

FIG. 10 is a bar graph showing the effect of electrical stimulation onin vitro production of GLP-1 by differentiated NCI-H716 cells.

FIG. 11 is a time course graph showing the effect of electricalstimulation on in vitro production of GLP-1 by differentiated NCI-H716cells.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments described herein provide methods and apparatus forstimulating cells in the small intestine to secrete glucagon-likeproteins (also referred to herein as glucagon-like peptide) and otherhormones and secreted compounds for the treatment of various conditionsincluding diabetes and obesity.

Referring now to FIGS. 1-3, the mucosal surface of the intestinal tractincluding the small and large intestine are lined with a number ofcells, including L-Cells (LC) and K-cells (KC). The L-cells include asub-mucosal portion SP and a luminal projecting portion LP which extendsfrom the surface of the mucosa M and binds with various moleculesincluding glucose. L-cells and K-cells secrete various gastrointestinalhormones known as incretins including glucagon like protein (GLP-1),glucose-dependent insulinotropic peptide GIP and oxyntomodulin (OXM).

The hormone GIP can enhance secretion of GLP-1. GIP is secreted byso-called “K” cells in the proximal duodenum, under some degree ofcontrol by enteric cholinergic neurons. The L-cells as well as K-cellssecrete GLP-1 and GIP in response to exposure to glucose. In turn, GIPacts to increase release of GLP-1. GLP-1 in turn, acts to increase theproduction of insulin as is discussed below. Incretins produce otherbeneficial effects such as appetite suppression, weight loss,restoration of insulin-sensitivity of body tissue and preservation ofbeta-cells of the pancreas. Incretins are rapidly metabolized/degradedby the kidney and peptidases (half-life GLP-1<2 mins, GIP<7 mins.).

Incretins are thought to play an important role in glucose controlwithin the body in that incretins such as GLP-1, increase insulinsecretion in a glucose dependent manner in a phenomenon known as the“incretin effect.” In fact, approximately 50% or more of the insulinresponse to a meal is attributed to the incretin effect. The incretineffect causes a fairly rapid increase in plasma insulin, usually withinabout the first 30 minutes after ingestion of glucose. Many patientswith type 2 diabetes have a significant reduction of the incretin effectincluding a reduction in GLP-1 secretion and a substantial reduction inthe insulinotropic activity of GIP. This results in a substantialreduction in the rate and amount of insulin production in diabeticpatients.

Several approaches can be contemplated for reversing the loss of theincretin effect occurring in diabetes including Type II diabetes. Theseinclude increasing the production of GIP and/or GLP-1. As discussedabove, in patients with Type II diabetes, GIP loses its insulinotropicactivity and is thus no longer able to modulate glucose-dependentinsulin secretion, even at supraphysiological (pharmacological) plasmalevels. The loss of this activity is detrimental to the production ofinsulin by the .beta.-cells of the pancreas, especially after eating.Therefore, increasing GIP production may not be a viable option.However, GLP-1 is still insulinotropic in Type II diabetes, albeit withsignificantly reduced levels. Therefore, increasing levels of GLP-1appears to be an approach for increasing insulin production in diabeticpatients including patients with Type II diabetes.

Accordingly, various embodiments of the invention contemplate increasingthe production of GLP-1 and other incretins by electrically stimulatingportions of the intestines concurrently or substantially concurrently tothe ingestion of a meal. This can be achieved by ingesting a swallowablecapsule before, during or after the ingestion of a meal, wherein thecapsule is configured to electrically stimulate portions of theintestine to stimulate L-cells to secrete GLP-1 and other incretins toincrease insulin production. Desirably, the capsule is swallowed in acoordinated fashion with the ingestion of a meal (e.g., during aselected time before, during or after the ingestion of a meal, e.g.,1-30 minutes before or after the ingestion of a meal) such thatsecretion of GLP-1 or other incretin is coordinated with the absorptionof nutrients into the blood stream. The coordination or timing of thecapsule with the ingestion of a meal can also be selected to produceother effects such as appetite suppression described herein.

Referring now to FIGS. 4-8, an embodiment of a swallowable capsule 10for stimulating L-cells and other cells in the intestinal tract IT tosecrete incretins includes a capsule body 20, at least two or moreelectrodes 40 for providing electrical stimulation to desired cells, acontroller 30 for controlling one or more operations of the capsule andgenerating the electrical signals delivered to the tissue by theelectrodes, a power source 55 for powering one or more components of thecapsule such as the controller and at least one sensor 60 fordetermining the location of the capsule in the tract and/or variousevents and conditions in the GI tract. In various embodiments discussedherein, capsule 10 may also include an accelerometer 65 for measuringthe rate of travel of the capsule through the intestinal tract IT anddetermining periods of no movement.

Capsule body 20 (herein referred to as body 20) is desirably sized andshaped to be swallowed by the user (also referred to herein as thepatient) and pass completely through the intestinal tract with normalperistaltic movement. Body 20 includes a body surface 25 and interiorcavity 21 for various components, e.g., controller 30, etc. Body 20 canbe fabricated from various biocompatible inert plastics known in the artand can also include various coatings (e.g., enteric coatings).

Electrodes 40 can comprise various biocompatible conductive materialsincluding silver-silverchloride, platinum or stainless steel. Stillother conductive materials known in the art, such as various conductivepolymers are also contemplated. Electrodes 40 can also have a laminatedconstruction with a more corrosion resistant material on the surface.Typically, electrodes 40 will include at least one electrode pair 50 ofelectrodes which can be configured as bipolar electrodes. Multiple pairs50 of electrodes 40 are contemplated including two, three, four andstill larger numbers.

Electrodes 40 can be positioned in a variety of manners on the surface25 of the capsule body 20. This includes in a lengthwise fashion withrespect to radius 20 r of the capsule, as is shown in embodiment of FIG.7a . FIG. 7a also shows an embodiment where electrodes 40 comprise oneor more pairs 50 of ring electrodes 40 r which are placed on the surfacecapsule. Multiple pairs 50 of ring electrode 40 r can be distributedalong the length of the capsule 20 with each pair being switchable bycontroller 30 or other switching circuitry. Such embodiments allowcontroller 30 to switch individual electrode pairs 50 on and off so asto optimize the stimulation of L-cells based on a variety of factors,for example, when a peristaltic contraction or squeeze is detected onone portion of the capsule, but not another.

In other embodiments, electrodes 40 can be oriented in a lengthwisefashion with respect to the longitudinal axis 20L of the capsule 20 asis shown in the embodiment of FIG. 7b . In preferred embodiments,capsule 20 can include multiple pairs 50 of electrodes 40 oriented withrespect to lateral axis 20L so that they are distributed around thecapsule perimeter 20 p as is shown in the embodiment of FIG. 7c . Instill other embodiments, capsule 20 can include a combination oflaterally and radially oriented electrodes as is shown in the embodimentof FIG. 7d . Such embodiments can be used for stimulating differenttypes of cells (e.g., L-cells and K-cells), cells in differentlocations, or as is discussed herein, for stimulating L-cells and alsostimulating intestinal muscle tissue to evoke a peristaltic contraction.

Desirably, the spacing or gap 45 between individual electrodes isconfigured to minimize electrical stimulation of tissue subjacent themucosal layer of intestinal tract as is shown in the embodiment of FIG.6. The spacing 45 can be configured to limit the electrical stimulationof the intestinal wall to a depth of 5 mm or less more preferably 3 mmor less and still more preferably 1 mm or less. In particularembodiments, gap 45 can be in the range from about 0.05 to about 0.2inches with specific embodiments of 0.1, 0.15 inches. Closer spacing canbe used to achieve a shallower stimulatory effect. Particular embodimentcan have varied spacing between electrodes pairs 50 with some pairsconfigured for a shallower stimulatory effect and others configured fora deeper stimulatory effect. In the latter case, the deeper stimulatoryeffect can be configured for stimulating the intestinal muscle tissue toevoke a peristaltic contraction of the intestine as is discussed herein.

Power source 55 will typically comprise a miniature chemical batterysuch as a lithium or lithium-ion battery. For battery embodiments ofpower source 55, the battery can be configured to provide at least 5 ormore hours of battery life. Controller 30 can include various powermanagement circuitry to optimize battery life. In various alternativeembodiments power source 55 can also comprise a piezo-electric powersource that uses piezo electric materials configured to harvest energyfrom compression or deformation of the capsule by movement of thecapsule through the intestinal tract. In still other embodiments, thepower source can comprise a thermo-electric power source such as apeltier effect power source device configured to use heat from thepatient's body to generate power. In such embodiments, all or a portionof the capsule can include a thermally conductive layer or other thermalconductive element configured to conduct heat to the peltier effectdevice.

In various embodiments, the at least one sensor 60 can include one ormore of a pH sensor and a pressure/force sensor. The pH sensor can beconfigured for detecting passage of the capsule from the stomach intothe small intestine, as indicated by a rapid rise in pH when the capsulepasses through the pyloric valve and into the duodenum. Variousminiature pH sensors known in the art can be utilized. The pressuresensor 60 can be utilized for sensing the peristaltic contraction of theintestines so as to detect when the capsule is in the intestine. Thepressure sensor 60 can be used to detect when intestine is in contactwith capsule (e.g., when it's being squeezed during a peristalticcontraction or peristaltic squeeze) and thus when to initiate a periodof stimulation. Various miniature solid state pressure/force sensors canbe used such as various miniature strain gauge sensors including variousmicro-electrical-mechanical systems (MEMS) based strain gauges or otherrelated pressure/force sensor. Particular embodiments can include bothpH and pressure sensors so as to determine a change in pH from thestomach to the intestine and peristaltic contraction providing increasedlevel of accuracy in determining the position of the sensor within thetract. In various embodiment, multiple pH and pressure sensors 60 can bedistributed over capsule body surface 25 so as to determine when oneportion of the capsule has entered the intestine, or determine when oneportion is being squeezed by peristaltic contraction (and thuselectrodes in that section can be switched on) or other pressuredifferential inactive of a change in location or state of the capsule.

Still other sensors are contemplated, such as temperature, O₂, CO₂,optical, acoustical sensors, etc. Further, the inputs from multiplesensors may be combined to generate an aggregate sensory input for thecontroller to determine the position of the capsule. Also as isdiscussed herein, in various embodiments, sensor conditioning circuitry63 can be coupled to controller 30 to condition the sensor signals 61prior to being inputted to controller 30.

Referring now to FIG. 5, in one embodiment of a method of use, theswallowable capsule 10 of the present invention can be used tofacilitate insulin release and/or enhance its activity in the body. Uponingestion, the swallowable capsule 10 makes its way through the stomachinto the small intestine SI. Sensors 60 in the capsule 10 allow itsrelative position in the body to be detected. For example, sensors forpH, pressure, or other pertinent indicia allow the capsule to determinewhen it has gone past the pyloric sphincter and reached the smallintestine. In the case of pH measurements, this can be determined by asharp rise in pH occurring after the capsule has gone past the pyloricsphincter and into the duodenum.

Once in the small intestine, swallowable capsule 10 is activated toprovide electrical stimulation so that L-cells of the small intestinesecrete GLP-1 or other incretins (GIP, PYY, etc.). The GLP-1 and/orother incretins then elicit secretion of insulin and/or facilitate thebody's use of insulin. Activation of the swallowable capsule to provideelectrical stimulation may, for example, be directed by internalinstructions and/or programs within the controller or other logicresources disposed in the swallowable capsule, or may be provided byexternal control of the swallowable capsule.

Because in some patients, the L-cells tend to be more concentrateddistally, (particularly in diabetic patients who have an unevendistribution with the majority located distally) the capsule controller30 may, in particular embodiments, initiate a timer upon reaching thesmall intestine so that the controller may estimate how far the capsulehas traveled in the small intestine. This distance can be estimated withthe use of average transit times through the gut or an individualmeasurement of transit time for the particular patient using knownmethods in the GI diagnostic arts. Appropriate delays in the initiationof stimulation can then be determined using the timer function. Longerdelays can be used for patients having longer transit times. Inembodiments having an accelerometer, the actual speed of the capsulethrough the intestine can be calculated and utilized to determine whento initiate a stimulation signal after the capsule has entered into thesmall intestine. Also as discussed below, adjustments in the timing ofthe L-cell stimulating signal can be made for embodiments using aperistaltic contraction stimulating signal.

As an alternative or adjunct to the use of a pH sensor for determiningcapsule position including when the capsule has entered the smallintestine, capsule 10 can also include a pressure sensor 60 to detectwhen the intestinal walls are squeezing the capsule e.g., from aperistaltic contraction. Appropriate pressure/force levels indicative ofintestinal squeezing can be determined from known physiologicalmeasurements or can established by looking for a relative increase insqueezing pressure (e.g. 2', 3×, 5× or an order of magnitude or more).In some embodiments, the detection of squeezing by the intestinal wallcan also serve as a trigger to initiate electrical stimulation of theL-cells as it may be desirable to have the electrodes in contact with orotherwise close to the intestinal walls. Such contact or proximity mayserve to more effectively deliver current to, and depolarize, theL-cells to produce GLP-1. Also, in related embodiments, once a decreasein pressure is detected (indicating a relaxation of the intestinal wallaway from the capsule), electrical stimulation can be stopped (eitherinitially or after a programmed delay) so as to conserve battery powerduring a time when stimulation may produce a sub-optimal release ofGLP-1 or other incretin. Thus in this way, the stimulating signals fromthe electrodes can be turned on and off with each peristalticcontraction of the intestine (either the small or large intestine) untilthe capsule has transited all or a selected portion of the intestine.

Preferably, the swallowable capsule is ingested with a meal so that thestimulation of the L-cells (or other cells) to secrete GLP-1 and/orother incretins is coordinated with absorption of nutrients from themeal so that subsequent insulin production is also coordinated with theinflux of glucose, fats and other nutrients into the blood stream. Inthis way, insulin is delivered in a manner to mimic normal physiologicdelivery of insulin upon digestion of food and thus achieve improvedblood glucose management. This process can be refined even further byusing standard glucose monitoring methods (e.g., a blood glucose meter)to monitor blood glucose levels following a meal and then makeadjustments in the delay or other timing of the stimulation signal. Insome embodiments, the capsule can be configured to allow the user toinput to the capsule, the amount and type of food being consumed (e.g.,a high carbohydrate or high fat meal, which is more likely to produce aspike in blood glucose). A software module resident within or coupled tocontroller 30 or other logic resources within capsule 10 can then adjustthe timing and sequence of the L-cell stimulating signal so as totitrate the levels of generated insulin in response to food consumed.The inputs to the capsule can be signaled by a handheld device such as acellular phone or like device using BLUETOOTH or other wirelessconnectivities or protocols known in the art. In these and relatedembodiments, capsule 10 can include an RF-communication chip.

Referring now to FIG. 8, embodiments of a circuit architecture 100, forcontrolling one or more functions of capsule 10 will now be discussed.Architecture 100 will typically comprise a controller 30, sensors 60(such as pressure and pH sensor), sensor conditioning circuitry 63, astimulation signal source 70 (herein signal source 70), an H-bridge orlike device 80. Controller 30 will typically comprise a microcontrollersuch as a microprocessors or state device and can be coupled to one ormore other electronic components of capsule 10 as is shown in theembodiment of FIG. 8. Also as shown in the figure, power source 55 canbe coupled to one or more components of architecture 100, (e.g.,controller 30, sensor 60, stimulation signal source 70, etc.) so as toprovide power to those components. Sensor conditioning circuitry 63 caninclude standard circuitry known in the art and serves to condition(e.g., filter via high pass or low pass filter) inputs 61 received fromsensors 60. Signal source signal 70 comprises a variety of energyconversion circuits that translates a fixed DC voltage from a battery orother power source 55 into a programmable energy modality. Suitableenergy conversion circuits for signal source 70 can include one or moreof the following: a programmable current source, programmable voltagesource, a DC-DC converter or a DC-AC converter. H-bridge device 80supplies signals to electrodes 40 and can be configured to change thedirection of current flow between electrodes 40 so as to produce abiphasic stimulation signal (described below) as well as stop the flowof current altogether (via means of one or more switches actuable bycontroller 30).

Collectively, controller 30, stimulation signal source 70 and H-bridge80 comprise a signal generator 110, also known as waveform generator 110which generates stimulation signals 200 that are delivered to electrodes40 and then conducted to intestinal tissue (e.g., the intestinal wall)for stimulating L-cells (or other cells) for producing incretins such asGLP to stimulate insulin production or enhance the effect of insulin.Desirably, signal 200 is configured such that it will stimulate theL-cells to produce incretins such as GLP-1 but will not causeperistaltic contractions of the intestinal site near the capsule 200 orany other location in the intestinal tract. This quality can be achievedby control of one or more of the current, voltage and/or frequency ofthe signal as well as pulse duration for pulsed signals as describedherein. For L-cell (and K-cell) stimulating purposes, signals 200 canhave voltages ranging from about 0.1-10V, currents ranging from about 10μa to 2 mA and frequencies ranging from 1 Hz-100 Hz. Voltage, currentand frequency can also be fine tuned or otherwise adjusted for thecondition to be treated (e.g., diabetes, obesity, etc.), the severity ofthe condition (e.g., type I vs. type II diabetes) and other patientconditions (such as intestinal neuropathy).

Signals 200 can have a variety of waveforms such as square wave, sinewave, saw tooth, trapezoidal, for example. In preferred embodiments,signal 200 can comprise a biphasic signal 200 b, which can be generatedusing an H-bridge device 80 as is described above. In many embodiments,including those having a square waveform signal 200 can comprise apulsed signal 200 p. Pulsed signals 200 p can have pulse widths rangingin the range of 10 μs-100 ms.

As described above, the signal 200 is desirably configured such that itwill stimulate L-cells (or other related cells such as K-cells) toproduce incretins such as GLP-1 but will not cause peristalticcontractions of the intestinal site near the capsule or any otherlocation in the intestinal tract. However in some embodiments, waveformgenerator 110 can also be configured to produce two waveforms, a firstwaveform 200 for stimulating the L-cells without causing peristalticcontractions and a second waveform 210 for causing peristalticcontractions so as to advance capsule 10 along the intestinal tract. Inthese later embodiments, the capsule can include an accelerometer 65 fordetecting when the capsule 10 has stopped moving or is moving below adesired velocity threshold. In use, these latter embodiments allow forcapsule 10 to be advanced in patients who have a very slow movingintestinal tract such as those patients who have intestinal neuropathyor other related condition such as intestinal necrosis. When controller30 receives an input 66 from the accelerometer 65 indicating thatcapsule 10 has stopped or is moving too slow the controller can producea signal for the waveform generator 110 to generate the second waveform210 causing peristaltic contraction of the intestine in the region nearthe capsule which, in turn, propels the capsule distally through theintestine. The process can be repeated as needed with selectable delaysto allow for the refractory period of the peristaltic contraction.

Referring now to FIGS. 9a-9d , a discussion will now be presented of anembodiment of a method for propelling the capsule through the intestineby evoking peristaltic contractions. As discussed herein, some patients,particularly diabetic patients, have a condition known as intestinalneuropathy wherein the transit time of food through the small and/orlarge intestine is greatly reduced due to damage of the motor neuronsinnervating the intestine. Accordingly, in particular embodiments, thecontroller can also be configured to produce two stimulating signals,one signal having a first waveform for stimulating the L-cells withoutcausing peristaltic contractions and a second signal having a secondwaveform for evoking peristaltic contractions so as to advance thecapsule along the intestinal tract. As discussed herein, the secondsignal can have higher stimulation currents than the first signal, forexample, in the range of 2-5 ma. In embodiments using a peristalticstimulating signal, capsule 10 can include an accelerometer 65 fordetecting when the capsule has stopped moving or is moving below adesired velocity threshold. When controller 30 detects that the capsuleis below a desired threshold or that that the capsule has beenstationary beyond a desired time period (e.g., 0.5 to 2 minutes withlonger and shorter periods contemplated), it initiates the generation ofone or more peristaltic stimulating signals to cause a peristalticcontraction to propel the capsule distally through the intestine. Anappropriate delay can then be built in before an L-cell stimulatingsignal is delivered to allow for the peristaltic contraction to occur aswell for the electrical refractory period of the intestine. If desired,multiple peristaltic evoking signals can be generated to cause a seriesof peristaltic contractions, for example, for patients who haveparticular slow transit time or when the capsule is just entering thesmall intestine so as to move the capsule more distally within theintestinal tract before L-cell stimulating signals are delivered. Inuse, such embodiments allow for the capsule to be advanced in patientswho have a very slow moving intestinal tract such as those patients whohave intestinal neuropothy or other related condition such as intestinalnecrosis. When the controller receives an input from the accelerometerindicating that the capsule has stopped or is moving too slow, thecontroller generates the second waveform causing peristaltic contractionof the intestine in the region near the capsule which in turn propelsthe capsule distally through the intestine. The process can be repeatedas needed with selectable delays to allow for the refractory period ofthe peristaltic contraction.

EXAMPLES

Various embodiments of the invention will now be further illustratedwith reference to the following examples. However, it will beappreciated that these examples are presented for purposes ofillustration and the invention is not to be limited by these specificexamples or the details therein.

Example 1—Electrical Stimulation of In Vitro GLP-1 Release

Culture dishes were coated on ice with Matrigel by adding 50 ul/cm² (190ul in 24 well dishes). The dishes were warmed at 37° C. for 30 minutes,and then seeded with 260,000 cells using high glucose DMEM supplementedwith 2 mM glutamine (0.146 g per 500 ml), 10% fetal bovine serum (FBS),and 1% Pen Strep. After 48 hours there were 1.5-2 million cells perwell. The initial cells were NCI-H716 cells, which are a human poorlydifferentiated colorectal adenocarcinoma. These cells grewundifferentiated in suspension. However, after the 48 hour treatmentdescribed above, the cells differentiated into GLP-1 secreting cells.These GLP-1-secreting cells were used for the following experiment.

For the experiment, the cell medium was replaced with HBSS supplementedwith 0.5% FBS and optionally one of the following test agents:

-   1. PMA (phorbol-12-myristate-13-acetate) (stock solution of 1 mg in    1.6 ml DMSO=1 mM; add 1 ul per ml of media, giving a final    concentration of 1 uM)-   2. 1.5% sucrose-   3. 10% glucose-   4. Electrical stimulation (250 uA, 5 Hz, alternating pulse wave of    0.1, 1.0 or 10 msec)

The cells were cultured for 2 hours. Test agents were added and cellsupernatants were removed at various time points for analysis. PMSF (10ul) was added to the cell supernatants, which can be frozen or usedimmediately. A lysis buffer was prepared by combining RIPA with 10 ulPMSF, 10 ul proteinase inhibitor, and 10 ul sodium orthovate. 200-300 ulof the RIPA lysis buffer was then added to a well along with the cellsupernatant sample. The well was scraped with a cell scraper and themixture was pipetted into a 1.5 ml tube, followed with repipetting tobreak up cells and cell membranes. The tubes were spun down at fullspeed for 5 min, the supernatants were collected and then frozen orimmediately analyzed.

GLP-1 was determined by ELISA. Streptavidin coated wells were incubatedwith a biotin-conjugated antibody which specifically binds GLP-1. Afterincubation with the lysed cell supernatants, the samples were thenincubated with GLP-1-binding antibody conjugated to HRP (horseradishperoxidase). Substrate conversion by HRP was then used to quantitateGLP-1. The results are shown in FIGS. 10 and 11.

CONCLUSION

The foregoing description of various embodiments of the invention hasbeen presented for purposes of illustration and description. It is notintended to limit the invention to the precise forms disclosed. Manymodifications, variations and refinements will be apparent topractitioners skilled in the art. For example, the capsule can be sizedfor various pediatric applications. Also the waveform can be configuredto inhibit as well as stimulate various cells in the intestinal tract.For example, the waveform can be configured to stimulate one cell typeand inhibit another. Additionally, various embodiments of the capsulecan include telemetry for signaling to and from an external monitoringand/or control device.

Elements, characteristics, or acts from one embodiment can be readilyrecombined or substituted with one or more elements, characteristics oracts from other embodiments to form numerous additional embodimentswithin the scope of the invention. Moreover, elements that are shown ordescribed as being combined with other elements, can, in variousembodiments, exist as stand-alone elements. Hence, the scope of thepresent invention is not limited to the specifics of the describedembodiments, but is instead limited solely by the appended claims.

What is claimed is:
 1. A method for electrically stimulating hormoneproducing cells (HP-cells) in the intestinal tract of a patient tosecrete a glucose regulating hormone (GR-hormone), the methodcomprising: delivering a device to the intestinal tract of the patientto electrically stimulate the HP-cells in the intestinal tract; anddelivering an electrical signal from the device to an intestinal wallproximate the device, wherein the signal includes a waveform configuredto electrically stimulate HP-cells in the intestinal tract to secretethe GR-hormone with normal peristaltic contraction of the intestinaltract wherein the electrical signal includes a first wave form and asecond waveform, the first wave form configured to stimulate theHP-cells without causing a peristaltic contraction the determination ofsuch made by sensing a pressure of the intestinal wall on the device. 2.The method of claim 1, wherein the intestinal wall is a wall of thesmall intestine.
 3. The method of claim 1, wherein the HP-cells compriseK-cells or L-cells.
 4. The method of claim 1, wherein the secretedGR-hormone comprises an incretin or GLP-1.
 5. The method of claim 1,further comprising: modulating a release of insulin in the patientresponsive to the secreted GR-hormone.
 6. The method of claim 5, whereinthe insulin release is modulated by the electrical stimulation of theHP-cells to produce an increase in plasma insulin within 30 minutes ofstimulation.
 7. The method of claim 1, further comprising: controlling ablood glucose level of the patient responsive to the secretedGR-hormone.
 8. The method of claim 1, further comprising: suppressing anappetite level of the patient responsive to the secreted GR-hormone. 9.The method of claim 1, wherein the waveform has a square wave shape. 10.The method of claim 1, wherein the pressure is sensed by a pressuresensor associated with the device.
 11. The method of claim 1, whereindelivering the device to the intestinal tract comprises ingesting thedevice.
 12. The method of claim 11, wherein the device comprises aswallowable capsule.
 13. The method of claim 11, wherein the ingestionof the device is coordinated with a ingestion of food.
 14. The method ofclaim 11, wherein the device is ingested during a selected time periodbefore, during or after the ingestion of food.
 15. The method of claim14, wherein the time period is selected to coordinate the stimulation ofthe HP-cells with the absorption of nutrients from the food into a bloodstream.
 16. The method of claim 11, wherein the device travels throughthe intestinal tract to stimulate HP-cells at any location where theyare found in the intestinal tract.